ライフサイエンスコーパス: APL

1 APL blasts overexpress annexin II (ANXII), a receptor fo

2 APL cell treatment with all-trans-retinoic acid (RA) deg

3 APL cells from these mice were responsive to all-trans r

4 APL externalization occurs in numerous events, and it is

5 APL is exquisitely sensitive to retinoic acid (RA) and a

6 APL is most commonly caused by a translocation (15:17) a

7 APL is remarkable because of the fortuitous identificati

8 APL neurons contact DPM neurons most densely in the alph

9 APL was chosen as a model disease because of the potenti

10 n CACNG3 (rs757200 nonparametric LOD* = 3.3, APL (association in the presence of linkage) P = 0.06, a

11 k circuit showed that Kenyon cells activated APL and APL inhibited Kenyon cells.

12 hort-lived effector cells in response to all APLs but also were characterized by diminished cytokine

13 Aminophospholipid (APL) trafficking across the plasma membrane is a key eve

14 sures externalization of aminophospholipids (APLs) to the outside of the plasma membrane using mass s

15 elimination of competing T cells bestowed an APL with the ability to expand naive encephalitogenic T

16 ghput bisulfite sequencing, we identified an APL-associated hypermethylation at the upstream differen

17 t and intriguing experiments performed in an APL mouse model, they demonstrate that supplementation w

18 heterogeneity prevented the selection of an APL candidate for developing an improved generic gp100 v

19 In the present study, we used an APL mouse model to study ANXII function and the effects

20 r incidence of B-cell ALL/L (IRR = 1.64) and APL (IRR = 1.28); blacks had lower IRs of nearly all AL

21 t showed that Kenyon cells activated APL and APL inhibited Kenyon cells.

22 ne or both domains decreased APL binding and APL-dependent catalytic activity of nSMase2.

23 omyelocytic leukemia (APL)-derived cells and APL primary cells, and PML-Fas complexes in normal tissu

24 re reduced in PML/RARalpha knock-in mice and APL patient samples.

25 fects of UBP43 on PML/RARalpha stability and APL growth, apoptosis, or differentiation.

26 analysis of interactions between nSMase2 and APLs will contribute to our understanding of signaling p

27 In contrast, arsenic, the other potent anti-APL therapy, only induces PML/RARA degradation by specif

28 the absence of antiphospholipid antibodies (APL).

29 pirical discoveries that PML-RARa-associated APL is sensitive to both all-trans-retinoic acid (ATRA)

30 -181b as oncomiRs in PML/RARalpha-associated APL, and they reveal RASSF1A as a pivotal element in the

31 pplied to other cell events characterized by APL externalization, including cell division and vesicul

32 for the cooperative activation of nSMase2 by APLs.

33 Disrupting the Kenyon cell-APL feedback loop decreased the sparseness of Kenyon cel

34 copy number analysis of a well-characterized APL mouse model to uncover somatic mutations in Jak1 and

35 However, previously published childhood APL studies have generally analyzed all patients age < 1

36 th newly diagnosed and genetically confirmed APL consecutively treated at a single institution.

37 ade PML/RARA oncoprotein and, together, cure APL.

38 r, mutation of one or both domains decreased APL binding and APL-dependent catalytic activity of nSMa

39 These mice developed APL indistinguishable from wild-type PR, but with signif

40 erm outcome of patients with newly diagnosed APL treated at our institution on 3 consecutive prospect

41 free survival in adults with newly diagnosed APL.

42 Differentiated APL blasts sorted from uncoupled retinoid-treated mice r

43 of deletion mutants identified two discrete APL binding domains in the N terminus of nSMase2.

44 egradation by arsenic trioxide, an effective APL treatment.

45 l activation, explaining how arsenic elicits APL maturation through PML/RARA degradation.

46 demonstration of a population of exclusively APL-specific T cells, (ii) an experiment in which an enc

47 the APLs capable of stimulating exclusively APL-specific T cells are able to expand encephalitogenic

48 Thus, the molecular species of externalized APL during platelet activation, apoptosis, and energy de

49 In this protocol, externalized APLs are chemically modified by using a cell-impermeable

50 ich produce high levels of the extracellular APL-1 fragment, show an incompletely penetrant temperatu

51 lead to new findings such as biomarkers for APL and additional molecular targets for arsenic trioxid

52 ranscriptional activation is dispensable for APL eradication.

53 Among AML subtypes, survival was highest for APL and AML with inv(16).

54 Thus, differentiation is insufficient for APL eradication, whereas PML/RARA loss is essential.

55 uced by A9/I-A(q), nor are they required for APL stimulation of cytokines.

56 this study, the structural requirements for APL-selective binding of nSMase2 were determined and cha

57 Cells from APL patients showed increased genome-wide DNA methylatio

58 se of leukemic cells harvested directly from APL patients.

59 Blocking synaptic output from APL neurons after training disrupts labile memory but do

60 ose promoting phloem formation and function (APL, SUC2).

61 Furthermore, APL contacts MB neurons in the alpha' lobe but makes lit

62 body intrinsic neurons, as well as GABAergic APL neurons and local interneurons of the antennal lobes

63 DR4(+) melanoma patients for different gp100 APLs suggested highly variable TCR usage, even among six

64 is was demonstrated in U937/PR9 cells, human APL cells and transgenic mouse APL cells, in which PMLRA

65 In contrast, human APL is not associated with an antecedent stage of myelop

66 AK1 V658F mutation previously found in human APL and acute lymphoblastic leukemia samples.

67 ogic expression pattern of PML-RARA in human APL patients.

68 eflecting the clinical presentation of human APL.

69 able to those achieved in treatment of human APL.

70 f both humans and mice, and since some human APL samples contain TCR rearrangements and express T lin

71 nsortium on Acute Promyelocytic Leukemia (IC-APL) study.

72 nsortium on Acute Promyelocytic Leukemia (IC-APL) was established to create a network of institutions

73 nsortium on Acute Promyelocytic Leukemia (IC-APL), an initiative of the International Members Committ

74 The IC-APL formulated expeditious diagnostic, treatment, and su

75 The establishment of the IC-APL network resulted in a decrease of almost 50% in earl

76 e show that hypermethylation was acquired in APL in a monoallelic manner.

77 e fusion oncogene PML-RARA and treats APL in APL cell and animal models as well as in human patients.

78 to Fas and blocks Fas-mediated apoptosis in APL by forming an apoptotic inhibitory complex with c-FL

79 of arsenic trioxide to trigger apoptosis in APL cells.

80 c differentiation program induced by ATRA in APL.

81 ence of enhanced expression of miR-181a/b in APL patient specimens.

82 ring is now considered a standard of care in APL.

83 regulation of the miR-181a/b gene cluster in APL blasts and NB4 leukemia cells upon ATRA treatment as

84 -Myc lymphoma and induced differentiation in APL.

85 re accurately dissecting the early events in APL pathogenesis.

86 ress protein TRIB3 as an important factor in APL disease progression and therapy resistance.

87 a gene (PML)/RARalpha, which is generated in APL by chromosomal translocation.

88 In contrast, knock-down of Hdac1 in APL mice led to enhanced survival duration of the leukem

89 Next, inhibiting HK3 in APL cell lines resulted in significantly reduced neutrop

90 cysteinemia may reverse hyperfibrinolysis in APL.

91 s were preferentially DNA hypermethylated in APL cells.

92 n of senescence as a targetable mechanism in APL therapy.

93 o protected from aberrant DNA methylation in APL cells.

94 ain leads to overexpression of the miRNAs in APL.

95 approach to find other relevant mutations in APL.

96 n chromosome 14q32 are overexpressed only in APL.

97 tients, demonstrating the key role of PML in APL cure.

98 ion induction failure, is a high priority in APL, especially because such events represent a major ca

99 ated with a significantly worse prognosis in APL patients.

100 , the events that cooperate with PML-RARA in APL pathogenesis are not well understood.

101 Jak1 mutations to cooperate with PML-RARA in APL.

102 set of differentially methylated regions in APL was identified.

103 ferentiation syndrome and disease relapse in APL patients treated with AIDA protocols.

104 mportant determinant of clinical response in APL and may offer a therapeutic target for enhancing che

105 benefit conferred by uncoupled retinoids in APL mice is dramatically lower than the one provided by

106 suggested that ANXII plays a pivotal role in APL coagulopathy.

107 may have a role in exacerbating ER stress in APL cells.

108 nsible for the transcriptional impairment in APLs.

109 otein translation, to ATRA sharply increases APL cell killing to the extent that cures in this diseas

110 o PKA-II in attempts to enhance ATRA-induced APL maturation in a clinical setting.

111 gh this fusion oncogene is known to initiate APL in mice, other cooperating mutations, as yet ill def

112 st that PML-RARA requires DNMT3A to initiate APL in mice.

113 Interestingly, APL cells depleted of Hdac3 demonstrated a more differen

114 erative disease that ultimately evolves into APL.

115 s and the GABAergic anterior paired lateral (APL) neuron.

116 from the GABAergic anterior paired lateral (APL) neurons.

117 show that, in acute promyelocytic leukaemia (APL), ILC2s are increased and hyper-activated through th

118 engraftment of acute promyelocytic leukemia (APL) and myelofibrosis (MF) samples, and identified LICs

119 ome in primary acute promyelocytic leukemia (APL) and the role of promyelocytic leukemia-retinoic aci

120 monitoring in acute promyelocytic leukemia (APL) are available only in the context of conventional a

121 ed therapy for acute promyelocytic leukemia (APL) averages 70% at 5 years.

122 he dynamics of acute promyelocytic leukemia (APL) before and during therapy with regard to disease in

123 nd outcomes in acute promyelocytic leukemia (APL) between developed and developing countries.

124 t component of acute promyelocytic leukemia (APL) bleeding diathesis.

125 ic activity in acute promyelocytic leukemia (APL) but its activity in solid tumors remains to be expl

126 In most acute promyelocytic leukemia (APL) cases, translocons produce a promyelocytic leukemia

127 antly lower in acute promyelocytic leukemia (APL) compared with non-APL patient samples.

128 treatment for acute promyelocytic leukemia (APL) for more than a decade.

129 ) treatment in acute promyelocytic leukemia (APL) has been the paradigm of targeted therapy for oncog

130 Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia tha

131 Acute promyelocytic leukemia (APL) is a hematological malignancy driven by a chimeric

132 Acute promyelocytic leukemia (APL) is a malignancy of the bone marrow, in which there

133 L-RARA-induced acute promyelocytic leukemia (APL) is a morphologically differentiated leukemia, many

134 Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML).

135 A hallmark of acute promyelocytic leukemia (APL) is altered nuclear architecture, with disruption of

136 Acute promyelocytic leukemia (APL) is characterized by a blockade of granulocytic diff

137 Acute promyelocytic leukemia (APL) is characterized by granulopoietic differentiation

138 Acute promyelocytic leukemia (APL) is characterized by the t(15;17) translocation that

139 Acute promyelocytic leukemia (APL) is commonly complicated by a complex coagulopathy.

140 Acute promyelocytic leukemia (APL) is driven by a chromosomal translocation whose prod

141 chemotherapy, acute promyelocytic leukemia (APL) is now the most curable type of leukemia.

142 Acute promyelocytic leukemia (APL) is rare in children.

143 se majority of acute promyelocytic leukemia (APL) patients can be definitively cured by the combinati

144 Up to 15% of acute promyelocytic leukemia (APL) patients fail to achieve or maintain remission.

145 Acute promyelocytic leukemia (APL) remains the best example of a malignancy that can b

146 patients with acute promyelocytic leukemia (APL) remains unknown because of the paucity of outcome d

147 development of acute promyelocytic leukemia (APL) required DNMT3A.

148 -a therapy for acute promyelocytic leukemia (APL) that is considered the first example of targeted th

149 osed pediatric acute promyelocytic leukemia (APL) was a phase III historically controlled trial to de

150 Acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloi

151 In acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA) treatment induces g

152 In acute promyelocytic leukemia (APL), both isoforms are expressed, but their relevance i

153 In acute promyelocytic leukemia (APL), repression by the PML-RARalpha oncofusion protein

154 rd of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%.

155 ML/RARA-driven acute promyelocytic leukemia (APL), retinoic acid (RA) induces leukemia cell different

156 e diagnosis of acute promyelocytic leukemia (APL), with t(15;17)(q23;q21.1) in all metaphases.

157 on with Fas in acute promyelocytic leukemia (APL)-derived cells and APL primary cells, and PML-Fas co

158 causative for acute promyelocytic leukemia (APL).

159 ermediate-risk acute promyelocytic leukemia (APL).

160 prises as with acute promyelocytic leukemia (APL).

161 athogenesis of acute promyelocytic leukemia (APL).

162 ewly diagnosed acute promyelocytic leukemia (APL).

163 r treatment of acute promyelocytic leukemia (APL).

164 ermediate-risk acute promyelocytic leukemia (APL).

165 ewly diagnosed acute promyelocytic leukemia (APL).

166 oncoprotein of acute promyelocytic leukemia (APL).

167 thy present in acute promyelocytic leukemia (APL).

168 ted therapy in acute promyelocytic leukemia (APL).

169 development of acute promyelocytic leukemia (APL).

170 al effector of acute promyelocytic leukemia (APL).

171 nes and drives acute promyelocytic leukemia (APL).

172 e treatment of acute promyelocytic leukemia (APL).

173 ha)-associated acute promyelocytic leukemia (APL).

174 inical use for acute promyelocytic leukemia (APL); in our studies, ATO inhibited growth of Hh pathway

175 with relapsed acute promyelocytic leukemia (APL); its role as consolidation treatment for patients i

176 y equal IRs of acute promyelocytic leukemia (APL; IRR = 1.08).

177 ewly diagnosed acute promyelocytic leukemia (APL; see figure).

178 ; PML-RARalpha acute promyelocytic leukemia [APL] cells) and Emicro-Myc lymphoma in vitro and in vivo

179 ia and ATRA in acute promyelocytic leukemia [APL]).

180 cell death of acute promyelocytic leukemic (APL) cells by intercepting the degradation of nuclear co

181 Using altered peptide ligands (APLs) displaying high TCR affinities, we show that incre

182 Altered peptide ligands (APLs) were designed to enhance MHC binding and hence T c

183 Altered peptide ligands (APLs) with enhanced binding to MHC class I can increase

184 class II-restricted altered peptide ligands (APLs), which are normally protective in experimental aut

185 ggered T cells with altered peptide ligands (APLs).

186 and association in the presence of linkage (APL; GENECARD) and logistic regression (CATHGEN and aort

187 t between patients with M3V and classical M3 APL.

188 Sequencing of a mouse APL genome revealed 3 somatic, nonsynonymous mutations r

189 ere observed in 3 out of 14 additional mouse APL samples and 1 out of 150 human AML samples.

190 Kdm6a, also known as Utx) gene, in the mouse APL genome.

191 cells, human APL cells and transgenic mouse APL cells, in which PMLRARalpha recruited c-FLIP(L/S) an

192 In this study, using NB4 APL cell variants resistant to ATRA-induced differentiat

193 the ATRA-driven therapeutic response in non-APL AML.

194 translating ATRA/ATO-based strategies to non-APL acute myelocytic leukemia (AML) is currently lacking

195 lectrocardiograms from 113 patients with non-APL acute myeloid leukemia and myelodysplastic syndrome

196 However, among patients with non-APL AML, ATRA-based treatment has not been effective.

197 omyelocytic leukemia (APL) compared with non-APL patient samples.

198 e much more effective than the nonconjugated APL at inhibiting the development of experimental autoim

199 enhanced, compared with the nonpalmitoylated APL, and S-palm APL was taken up more rapidly into dendr

200 hods Patients age 2 to 21 years with de novo APL confirmed by PML-RARalpha polymerase chain reaction

201 In this large cohort of APL patients, high white blood cell count emerged as an

202 The known phenotypic constraints of APL could be explained by a combination of differentiati

203 tes fatty acids as molecular determinants of APL that regulate hemostasis.

204 gnized to be insufficient for development of APL, requiring acquisition of cooperating mutations.

205 A total of 1400 patients with a diagnosis of APL between 1992 and 2007 were identified.

206 ression during neutrophil differentiation of APL cell lines.

207 inding, inducing terminal differentiation of APL cells ex vivo or in vivo.

208 Dissection of APL pathogenesis has led to the rediscovery of PML bodie

209 Here we show that pan-neuronal expression of APL-1, the Caenorhabditis elegans ortholog of APP, disru

210 eural circuits, suggesting a broad impact of APL-1 on sensory plasticity in C. elegans.

211 udies using ATO in the primary management of APL, demonstrate the important role that ATO can play in

212 ration of ATO into the primary management of APL.

213 is considered in the clinical management of APL.

214 ate that in the Ctsg-PML-RARA mouse model of APL, PML-RARA is expressed in and affects the function o

215 To identify these, we used a mouse model of APL, whereby PML-RARA expressed in myeloid cells leads t

216 Multiple prior mouse models of APL constitutively express PML-RARA from a variety of no

217 the JAK/STAT pathway in the pathogenesis of APL and illustrate the power of whole genome sequencing

218 which has a key role in the pathogenesis of APL.

219 ylation is implicated in the pathogenesis of APL.

220 In the preleukemic phase of APL, Hdac1 counteracts the activity of PML-RAR in (1) bl

221 ink to the clinical hemorrhagic phenotype of APL.

222 of primary CD4(+) T cells in the presence of APL, with relative sparing of the central memory CD4(+)

223 r effect on early death and the cure rate of APL.

224 , is present on the extracellular surface of APL cells and is rapidly down-regulated in response to a

225 Treatment of APL blasts with all-trans retinoic acid also did not res

226 ith chemotherapy, the reference treatment of APL, is generally considered to produce similar results

227 f arsenic trioxide (ATO) in the treatment of APL.

228 sulted not only in a better understanding of APL itself, but also carry valuable lessons for other ma

229 rophil differentiation and cell viability of APL cells.

230 rowth inhibitory activities than curcumin on APL cells.

231 ed with the nonpalmitoylated APL, and S-palm APL was taken up more rapidly into dendritic cells and c

232 ase2 was dependent on anionic phospholipids (APLs).

233 In line with the observations in primary APL patient samples, we observed significantly higher HK

234 tis elegans encodes one APP-related protein, APL-1, which is essential for viability.

235 ells from an established transgenic PML-RARA APL mouse model at the orthologous region on chromosome

236 ce retain PML/RARA expression and reinitiate APL in secondary transplants.

237 We suggest that signaling of the released APL-1 fragment modulates multiple metabolic states and t

238 This unifying framework, which reproduces APL, normal progenitor, and differentiated granulocytic

239 tions previously identified in ATO-resistant APL patients are impeded in their ability to become sequ

240 pression of PHF8 resensitizes ATRA-resistant APL cells, whereas its downregulation confers resistance

241 differentiation in ATRA maturation-resistant APL cells.

242 h newly diagnosed, low- or intermediate-risk APL (WBC at diagnosis </= 10 x 10(9)/L).

243 nt of patients with low-to-intermediate-risk APL.

244 with ATRA-CHT in low- and intermediate-risk APL.

245 t in patients with low- or intermediate-risk APL.

246 ergy depletion (aging) externalized the same APLs in a calcium-dependent manner, and all stimuli exte

247 es ATRA-induced maturation in ATRA-sensitive APL cells (including NB4 cells) and restores it in some

248 Increased MHC binding of several APLs was observed, validating this approach biochemicall

249 acted specifically and directly with several APLs, including phosphatidylserine and phosphatidic acid

250 The modeling shows APL and normal states mutually suppress each other, both

251 Platelet-specific APLs optimally supported tissue factor-dependent coagula

252 ing a potential mechanism for high-stability APLs to enhance immunogenicity and accumulation of T cel

253 o establish panels of potential superagonist APLs to individualize tumor peptide vaccines among patie

254 We synthesized APLs and corresponding S-palmAPLs and showed that the S-

255 modulates multiple metabolic states and that APL-1 is required throughout development.

256 We demonstrate that APL may emerge from a dynamical endogenous molecular-cel

257 We propose that APL neurons provide widespread inhibition to stabilize a

258 Here, we show that APL-1 signaling is dependent on the activity of the FOXO

259 tion of calcium are clearly triggered by the APL A9/I-A(q) stimulation and are required for cytokine

260 at these two cytokines are important for the APL-induced attenuation of arthritis.

261 n conclusion, these data have identified the APL binding domains of nSMase2 for the first time.

262 The incidence of the APL differentiation syndrome was 26%, compared with 25%

263 ), as well as accelerated degradation of the APL-associated fusion oncoprotein PML/retinoic acid rece

264 These Envs used the APL-bound conformation of CCR5, were cross resistant to

265 is effectively outcompeted in vivo when the APL is used as the priming immunogen.

266 Our results show that although the APLs capable of stimulating exclusively APL-specific T c

267 its innate potential, then thiopalmitoylated APLs (S-palmAPLs) should show enhanced protective effect

268 Thus, APL differentiation is a default program triggered by cl

269 RARA haploinsufficiency would contribute to APL pathogenesis.

270 ml NB disruption is a central contributor to APL pathogenesis.

271 tand the contribution of molecular events to APL cell differentiation, leukemia-initiating cell (LIC)

272 somatic, nonsynonymous mutations relevant to APL pathogenesis, of which 1 (Jak1 V657F) was found to b

273 These events are not restricted to APL because lymphomagenesis driven by deletion of p53 or

274 n a transgenic mouse model of transplantable APL, and in the RA response of leukemic cells harvested

275 were preferentially up-regulated in treated APL cells, supporting the notion that the UPR was a cons

276 Upon treating APL with all-trans retinoic acid and achieving complete

277 d by the fusion oncogene PML-RARA and treats APL in APL cell and animal models as well as in human pa

278 1 patients (age >/= 15 years) with untreated APL to either a standard induction regimen of tretinoin,

279 Thus, using APL as a model, we uncover a tolerogenic pathway that ma

280 Conversely, using APLs displaying a decreased TCR affinity tilted our syst

281 Our results demonstrate that site V APLs cross-prime a higher fraction of available T cells,

282 r-dependent coagulation in human plasma, vs. APL with longer or shorter fatty acyl chains.

283 ventually approach the success achieved with APL, CML, and pediatric ALL.

284 e 6A (Kdm6a, also known as Utx) in mice with APL and validated the ability of Jak1 mutations to coope

285 Here we report a patient with APL who developed a mitochondrial myopathy after treatme

286 re well tolerated in pediatric patients with APL and allowed significant reduction in cumulative anth

287 nt after chemotherapy can cure patients with APL by eliminating the stem-like cell population over th

288 ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (white-cell c

289 and higher risk of relapse in patients with APL homogeneously treated with all-trans retinoic acid a

290 -based MRD monitoring study on patients with APL treated with a single agent ATO regimen.

291 enrolled low-intermediate risk patients with APL without any DNA-damaging chemotherapy.

292 For SR and HR patients with APL, the overall survival was 98% versus 86% ( P = .003)

293 o may be the first to evaluate patients with APL, to have a major effect on early death and the cure

294 elapse risk for both SR and HR patients with APL.

295 yeloid leukemia, including 231 patients with APL.

296 instituted when ATO is used in patients with APL.

297 uction, and following infection in vivo with APL-expressing bacteria, CD8 RTEs expanded to a greater

298 Adolescents and children age > 4 years with APL treated with ATRA and chemotherapy have outcomes at

299 were essential for nSMase2 to interact with APLs.

300 he clinicoradiological pattern of SS without APL (SSAPL- ) and its midterm prognosis.